The Role of Mendelian Randomization Studies in Deciphering the Effect of Obesity on Cancer

Associations of obesity have been established for at least 11 cancer sites in observational studies, though some questions remain as to causality, strength of associations, and timing of associations throughout the life course. In recent years, Mendelian randomization (MR) has provided complementary information to traditional approaches, but the validity requires that the genetic instrumental variables be causally related to cancers only mediated by the exposure. We summarize and evaluate existing evidence from MR studies in comparison with conventional observational studies to provide insights into the complex relationship between obesity and multiple cancers. MR studies further establish the causality of adult obesity with esophageal adenocarcinoma and cancers of the colorectum, endometrium, ovary, kidney, and pancreas, as well as the inverse association of early life obesity with breast cancer. MR studies, which might account for lifelong adiposity, suggest that the associations in observational studies typically based on single measurement may underestimate the magnitude of the association. For lung cancer, MR studies find a positive association with obesity, supporting that the inverse association observed in some conventional observational studies likely reflects reverse causality (loss of lean body mass before diagnosis) and confounding by smoking. However, MR studies have not had sufficient power for gallbladder cancer, gastric cardia cancer, and multiple myeloma. In addition, more MR studies are needed to explore the effect of obesity at different timepoints on postmenopausal breast cancer and aggressive prostate cancer.